Process for making crystalline cortisone acetate



PROCESS FOR MAKING CRYSTALLINE CORTISONE ACETATE .1

.1 Claim. (Cl. 260397.45)

This application is a division of application'Serial N0. 471,511, filed Nov. 26, 1954, now abandoned.

This invention relates to new crystalline forms of cor- .tisone acetate, tomethods for the preparation thereof and .toastable aqueous suspensions containing these new crystalline forms of cortisone acetate. Y

The preparation of stable aqueous suspensions of cortisone acetate has presented considerable difficulties. For example, after a relatively short period of time, aqueous suspensions of crystalline cortisone acetate are characterized by undesirable crystal growth, or -caking and sedimentation. Furthermore, these unstable suspensions cannot be rc-suspended by vigorous shaking and consequently their physical properties are altered to such a degree as to make them unsatisfactory for therapeutic use. For example, large crystals are a source of great irritation to patients and in addition cannot pass through fine hypodermic needles. In view of the paucity of information regarding ,the mechanism of crystal growth breaking and sedimentation inaqueous suspensions of cortisone acetate, the determination of the cause of or prevention of these undesirable physical phenomenahas been, extremely difficult. The problem is further complicated by the fact that cortisone acetate is 'now known to exist in various polymorphic forms, only oneofwhich has been known to produce stable, non-caking aqueous suspensions (U. S. Patent 2,671,750). v

Prior attempts to prepare crystalline cortisone acetate informs which are stable, i. e., characterized, by the absence of undesirable crystal growth, or caking and sedimentation, when suspended in an aqueous *medium, have been unsuccessful. For example, the preparation 'of'stable aqueous suspensionsof cortisone acetate of particle size suitable for injection by continuously. ballmilling unstable suspensions of cortisone acetate was unsatisfactory. When glass balls were used in *tlre'mill, these tended to fracture or wear down'andconsequently,

glass particles were found in the aqueous suspensions of cortisone acetate. Similarly, foreign particles were also found when alundum, porcelain or corundurn were substituted for glass. The use: of stainless steel -or :'chrom'e steel balls was likewise unsatisfactory since these -materials discolored the products. Attempts to .avoid these difliculties by stirring micronized cortisone acetate in an "aqueous vehicle for several days were usually unsuccess- United States Patent ice cortisone acetate. Other objects of the invention will 'besappar'ent to those skilled in the art to which this inventionjperta'ms. a r

. The invention provides new types of cortisone acetate in crystalline form and aqueous suspensions thereof which are characterized-by the absence of crystal growth. These preparations refsuspend easily even after extended periods of time and do not cake or clump.

The process for the preparation of new crystalline forms of cortisoneacetate comprises dissolving cortisone acetate in an inert water-miscible organic solvent, mixing the resulting solution with a second solvent selected from the group consisting of water and a water-immiscible hydrocarbon solvent fraction obtained from a petroleum distillate, said water-immiscible hydrocarbon solvent having a boiling point "between about 25 and about 150 degrees centigrade, in which the cortisone acetate is insoluble, to obtain new forms *of crystalline cortisone acetate.

In a more'specific embodiment of the invention, cortisone acetate, in any polymorphic'modification, is dissolved in a water-miscible organic solvent. .Suitable water-miscible organic solvents include methyl Cellosolve ,(ethylene glycol monornethyl ether), ethyl Cellosolve (ethylene glycol monoethyl other), Carbitol (d-iethylene glycol-monoethylether), Carbitol acetate, propylene .gly-

5001, ethylene glycol, .butylene-glycol, polyethylene glycols of molecular weight'between about 1500 and about6000, ethanol, dimethylacetamide, acetone, methanol, acetic acid, ,prop'anol, 'Z-propanol, ben-zyl alcohol, and therlike, the cellosolves such as methyl Cel'losolve, ethyl Cellosolve, and the like, being especially preferred. In dis- :solving the steroid in the water-miscible organic solvent,

' the use of heat, .i. e., temperatures :up to about the boil -ful regardless of crystal size of the micronized powder. W

Similar experiments using vehicles presaturated'w'ith. core. tisone acetate of various crystal formswere likewise.

only partially successful. 'The fact that these processes were not always reproducible madeithem impractical.

It is an object of the invention to .providenovel forms of crystalline cortisone acetate." Another object of the invention is to provide novel forms of crystaliine'cortisone acetate which will form stable, non-caking aqueous suspensions when suspended in 'an aqueous medium. 'Another object of the invention is'to provide methods for the preparation of these new crystalline forms of .ing-point of the mixture, is ordinarily preferred to facilitate the-dissolution of the cortisone acetate in the selected .solvent.

. After dissolving the cortisone acetate in the selected water-miscible organic solvent, the resulting solution is .then mixed with a second solvent in which the steroid is insoluble. The latter group of solvents include water and various hydrocarbon solvents boiling between about 25 degreesand about 150 degrees centigrade, obtained as fractions from petroleum distillates such as, for example,

Skellysolve A (essentially n-pentane) boiling between 2 and 38 degrees centigrade, "skellysolve A Special (essentially isopentane) boiling between 26 and 31 degrees centigrade,

Skellysolve B (essentially n-hexane) boiling between 60 and "71 degrees centigrade,

Skellysolve C (essentially n-heptane) boiling "between 85.

boiling between 40 and 75 degrees centigrade,

Skellysolve H (essentially light naphtha) boiling between 60 and degrees centigrade,

Skellysolve L (essentially a light lacquer diluent) boiling between 93 and 129 degrees centigrade,

.Skellysolve R (essentially a rubber solvent naphtha) boiling between 54 and 129 degrees centigrade, and the like.

I Whena solution of steroid in a water-miscible solvent of the water should be less than seventy degrees centigrade and preferably between about zero and about twenty degrees centigrade. On thoroughly mixing the steroid solution with water, a moist microcrystalline product is obtained which is designated as form A. The moist crystalline material is stable in aqueous vehicles. This product does not exist in dry form. The crystalline product is further characterized by the following X-ray diffraction data:

INTERPLAN AR SPACING, A.

The product significantly is not only stable in dry form but also in aqueous suspension and further, 98 percent of the crystals have a particle size between about forty and 10-10 about sixty microns in length.

While the X-ray difiraction pattern of form B is similar 5 to that of Merck form 1, it is to be noted that Merck form 15 1 is not stable in aqueous suspension. When the solution of cortisone acetate in a watermiscible organic solvent is mixed thoroughly with a hydrocarbon solvent obtained from a petroleum distillate as a fraction boiling between about 25 and 150 degrees centigrade, and in which the steroid is insoluble, and the The X ray data for this and other forms of cortisone resulting crystalline material separated and dried by conacetate indicated below were obtained by the powder ventlonal means new {nwrocrystanme q deslg' method using a Picker-Waite diffraction unit with nickel Pated as q C 1s The cryslanme. Producf filtered copper Kai radiation. The sample was prepamd is characterized by the following X-ray difiractlon data. by placing crystals in a suspension in a plastic capillary INTERPLANAR SPACING, tube sealed at one end with paraffin and alternately centrifuging and refilling to pack the moist crystals. The capillary tube was then sealed at the other end. Moisture transfer through the plastic capillary tube was controlled by maintaining a moisture-saturated atmosphere within the diffraction camera.

The crystalline product is clearly distinguishable from Merck form 5 (U. S. 2,671,750) in that the particle size of 98 percent of crystals is less than twenty microns in 35 length and further in that form A possesses an optic axial angle of five degrees while Merck form 5 possesses an optic axial angle of 69.5 degrees. The difierence in The product significantly is stable not only in dry form optic axial angle values is a significant and important but also in aqueous suspension and further, 98 percent difference in that the angle is a function of the three prinof the crystals have a particle size between about forty cipal refractive indices (optic axial angle, 2 V, is the and about sixty microns in length. smaller angle between the optic axes and lies in the optic While the X-ray diffraction pattern of form C is similar plane-Wahlstrom, Optical Crystallography, second edito that of Merck form 3, it is to be noted that Merck form tion, 1951, page 145). 3 is not stable in aqueous suspension.

On co-distilling the above described crystalline product When the cortisone acetate is dissolved in a polyethylene with a water-immiscible hydrocarbon solvent obtained glycol of a molecular weight between about 1500 and from a petroleum distillate as a fraction boiling between about 6000, the dissolution of the steroid in the solvent about 25 degrees and about 150 degrees centigrade, and being facilitated by heating at a temperature between in which the cortisone acetate is insoluble, and separatabout 180 and about 200 degrees Centigrade, and the ing and drying the resulting crystalline material by conresulting solution is cooled, a solid material is obtained. ventional procedures, the starting material is converted On mixing the solid material with Water, there is obtained A to a new form of crystalline cortisone acetate, designated a moist crystalline material which is identified as form as form B. The crystalline product is characterized by A. This product is identical with crystalline cortisone the following X-ray difiraction data: acetate form A described supra except for the fact that INTERPLANAR SPACING, A. 98 percent of thiscrystalline material has a particle size of less than ten lmcrons in length. 13,9 5,9 The various forms of cortisone acetate including Merck 10,7 5,5 form 5, disclosed in U. S. Patent 2,671,750, are further 6.83 5.12 characterized in the following table.

Form A Form B Form 0 Form 5 (U. S.

tifitfi b litaaa; EKIIIIZI i i B %Ztf Optic Sign Positive..- Positive. Dispersion None R V. Optic Axial Angle 5 69.5. Refractive Indices..

1.506. 1.532. 1.591. v b=X a/\Z=44 g z r' optic Orientatwn e) opticplane optic plan c optic plane= Refractive tndicee and optic orientation not obtainable because form A could not be obtained in a dry crystalline form.

The following examples illustrate the products and the methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration only and not by way of limitation.

Example I To twenty milliliters of methyl Cellosolve is added 5.2 grams of cortisone acetateNNR; The dissolution of the cortisone acetate in the solvent is facilitated by heating at a temperature of 100 degrees centigrade, The resulting solution is then sterilized by passing through a Hormann filter and using aseptic technique was slowly poured, while stirring, into 700 milliliters of sterile deionized water. After stirring for an additional fifteen minutes, the sterile suspension is filtered and washed with sterile deionized water.. A yield of 5.0 grams of moist microcrystalline'sterile cortisone acetate melting between 230 and 237 degreesand designated as form A is obtained. Ninety-eight percent of the} crystalline material has a particle size of less than twenty microns in length.

Following the procedure described above except for the replacement of methyl Cellosolve by other watermiscible organic solvents such as ethyl Cellosolve, Carbitol, Carbitol acetate, benzyl alcohol, propylene glycol, ethylene glycol, and the like, moist crystalline cortisone acetate, form A, is likewise obtained.

The sterile crystalline cortisone acetate thus obtained by aseptic processing was made up to a volume of 200 milliliters with a sterile vehicle containing, per milliliter,

Sodium carboxymethylcellulose hmilligrams Low viscosity sodium chloride do i 9 Tween-80 U. s.- P f do 4 Benzyl alcohol N. F d0 15.75 Deionized water q. s "milliliter" 1 The sterile suspension was then stirred for ten minutes in a sterile Waring blender. No crystal growth was noted in the suspension after storage for six months at temperatures of 25 degrees centigrade, forty degrees centigrade and 47 degrees centigrade. This suspension is suitable for intramuscular injection.

Exa pl 2 Fifty grams of cortisone. acetate NNR is dissolved in 500 milliliters ofmethyl Cellosolve. Heating at a temperature between 100 and 115 .degrees centigrade is utilized to facilitate the dissolution of the cortisone'acetate in the methyl Cellosolve. Three grams of Tween-80 (a polyoxyalkylene derivative of sorbitan monooleate) is added to the solution. To the resulting solution is added, accompanied by vigorous stirring, a cooled solution (four degrees centigrade) of three grams of Tween-80 in eight liters of deionized water. The resulting suspension is then filtered and the moist crystalline material thus obtained-is washed successively, two or three times, with two liters of deionized water. A yield of 45.0 grams of moist microcrystalline cortisone acetate is obtained as crystal form A. Ninety-eight percent of the crystalline product has a particle size of less than twenty microns in length.

To the moist-microcrystalline cortisone acetateis added a sufficient quantityof thevehicle described in Example 1 to make a total Volume of 1.5 liters. The suspension is passed through acolloid mill with a setting of 0.005" and the mill-is washed with asulficient quantityof vehicle to ive a final volume of 1.8 liters. The suspension is mixed thoroughly and then sterilized. The final product contains 25.0 milligrams of cortisone acetate per milliliter and has a pH of 5.9. Ninety-eight percent of the microcrystalline material has a particle size of less than twenty microns in length. After storage for six months at room temperature, the particle size of the microcrystalline cortisone acetate remained unchanged. The product is suitable for intramuscular injection.

6 Example 3 Twenty-five grams of cortisone acetate NNR is dissolved, while stirring, in 250 milliliters of methyl Cellosolve. Heating at a temperature between 110 and 115 degrees centigrade is utilized to facilitate the dissolution of the steroid in the solvent. The solution is then poured, accompanied by stirring, into 2.5 liters of Skellysolve B. The crystalline material thus obtained is then Washed with three 250-milliliter portions of Skellysolve B and then dried to a constant weight at a temperature between eighty and ninety degrees centigrade. There is obtained a yield of 23 grams of crystalline cortisone acetate, designated as form C, and further characterized by a melting point between 230 and 240 degrees centigrade, an ultraviolet extinction coefiicient E =l5,800 and an optical rotation [a] =+178 degrees (acetone). Ninety-eight percent of the crystalline material thus obtained has a particle size between about forty and about sixty microns in length.

.If the crystalline material supra is, only partially dried, a mixture of forms C and A is obtained. The mixture of forms C and A is stable in aqueous vehicles.

Following the procedure described above except for the replacement ofmethyl Cellosolve by other watermiscible organic solvents such as ethyl Cellosolve, Carbitol, Carbitol acetate, benzyl alcohol, propylene glycol, ethylenev glycol, and the like, and the substitution of Skellysolve B by other hydrocarbon solvents obtained from petroleum distillates as fractions boiling between about 25 and about 150 degrees centigrade such as Skellysolve A, Skellysolve C, Skellysolve D, Skellysolve E, Skellysolve F, and the like, cortisone acetate, form C is likewise obtained.

The microcrystalline cortisone acetate (form C) thus obtained is sterilized by the use of ethylene oxide gas and the following suspension is prepared:

Cortisone acetate, form C mi1ligrams 25 Sodium carboxymethylcellulose do 20 Sodium chloride do 9 Quatresin (myristyl gamma picolinium chloride) mil1igrams 0.233 Deionized water q. s milliliter 1 The sterile suspension thus obtained is repeatedly passed through a sterile colloid mill. There is no evidence of caking or crystal growth in the suspension after storage for six months at room or elevated temperatures. The suspension readily passes through a 21 gauge needle and is suitable for intramuscular injection.

and 115 degrees centigrade and 100 grams of cortisone acetate NNR is then dissolved therein, accompanied by stirring. Three grams of Tween is then added to the solution. The resulting solution is then mixed with a cooled solution (four degrees centigrade) containing 3.0 grams of Tween80 and sixteen liters of deionized water. The crystalline material thus obtained is removed from the suspension by filtration and then washed with three liters of deionized water. Five liters of Skellysolve B is added thereto and the solution is heated under reflux, accompanied by stirring, until water is no longer co-distilled with the Skellysolve B (a period between about six and about'eight hours). The suspension. is cooled to 25 degrees centigrade, filtered and then dried to constant weight in vacuo at eighty degrees centigrade. There is obtained grams of crystalline cortisone acetate, as crystal form B and characterized by a melting point between 236 and 245 degrees centigrade, optical rotation [0c] =+177 degrees (acetone) and an ultraviolet extinction E 15,350. Ninety-eight percent of the crystalline material thus obtained has a particle size between about forty and about sixty microns in length.

Following the procedure described above except for the replacement of methyl Cellosolve by other watermiscible organic solvents such as ethyl Cellosolve, Carbitol, Carbitol acetate, benzyl alcohol, propylene glycol, ethylene glycol, and the like, and the substitution of Skellysolve B by other hydrocarbon solvents obtained from petroleum distillates as fractions boiling between about 25 and about 150 degrees centigrade such as Skellysolve A, Skellysolve C, Skellysolve D, Skellysolve E, Skellysolve F, and the like, cortisone acetate, form B is likewise obtained.

The following vehicle is prepared:

Quatresin grams 4.43 Polyethylene glycol 4000 do 2280 Sodium citrate do 85.5 Neomycin sulfate do 114 Prophenpyridamine maleate NNR do 47.5 Deionized water q. s cc 18,900

The pH of the solution is adjusted between 6.0 and 6.5 with ninety percent phosphoric acid and the final volume of the resulting solution is adjusted to 19,000 milliliters.

Ninety-five grams of microcrystalline cortisone acetate, form B (supra), is added to the vehicle and the resulting suspension is passed through a colloid mill three times at a setting of 0.002". There is no evidence of caking or crystal growth in the suspension after storage for a year at room temperature. The suspension is suitable as a nosedrop preparation.

Example Eleven grams of cortisone acetate is dissolved in eighty grams of Carbowax 4000 (polyethylene glycol of molecular weight of 4000). To increase the rate of solution, gentle Warming and stirring are used. The resulting solution is then poured into 575 cubic centimeters of water (cooled to a temperature of twenty degrees centigrade). There is obtained crystalline cortisone acetate as crystal form A. Ninety-eight percent of the crystalline material has a particle size of less than ten microns in length. Except for the particle size, this product possesses characteristics identical with form A supra.

Following the procedure described above except for the replacement of Carbowax 4000 by Carbowax 1500, Carbowax 6000, and the like, cortisone acetate, form A is likewise obtained.

The microcrystalline cortisone acetate suspension thus obtained is preserved and made isotonic by the addition of 3.66 grams of chlorobutanol, 130 milligrams of Quatresin and three grams of sodium citrate. There is no evidence of crystal growth in the resulting suspension after storage for six months at temperatures of four degrees, 25 degrees and forty degrees centigrade. The suspension is suitable as a nosedrop preparation.

Example 6 Eleven grams of cortisone acetate and eighty grams of Carbowax 4000 are dissolved in 150 milliliters of methylene dichloride. Gentle warming and stirring are used to increase the rate of solution. The resulting solution is then filtered through a sintered glass funnel and washed with fifty milliliters of methylene dichloride. The solution thus obtained is then distilled to remove the methylene dichloride and the residue heated, with gentle stirring, to a temperature between 180 and 200 degrees centigrade (the use of methylene dichloride facilitates removal of foreign matter and also increases the rate of solution). The solution of cortisone acetate in Carbowax is then poured onto a well chilled smooth surface so that rapid solidification occurs. a a

The crystalline product is passed through a thirty mesh screen and then sterilized with ethylene oxide gas. Four grams of neomycin sulfate powder, blended, milligrams of Quatresin, 660 milligrams of polyvinyl pyrrolidone and three grams of sodium citrate are dissolved in 500 milliliters of water. The solution is then sterilized by passage through a Hormann filter and the sterile crystalline cortisone acetate obtained supra is added thereto. The resulting mixture is aseptically stirred at room temperature for fifteen to thirty minutes, diluted to a volume of 666 milliliters, passed through a sterile colloid mill, adjusted to a pH of 6.8 to 7.4 with a sterile five percent sodium hydroxide solution and then bottled in sterile vials. The product is a stable sterile suspension containing crystalline cortisone acetate, form A, 98 percent of said crystalline cortisone acetate having a particle size of less than ten microns in length. There is no evidence of crystal growth after storage for six months at temperatures of zero degrees, 25 degrees and forty degrees centigrade. The sterile suspension is especially suitable for ophthalmic use.

It is to be understood that various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the following claim, they are to be considered as part of the invention.

r We claim:

A process for the preparation of a new crystalline form of cortisone acetate which is stable in aqueous vehicles comprising dissolving cortisone acetate in an inert watermiscible organic solvent, mixing with water, adding to the mixture a water-immiscible hydrocarbon solvent fraction obtained from a petroleum distillate in which said cortisone acetate is insoluble, said water-immiscible hydrocarbon solvent having a boiling point between about 25 and degrees centigrade, co-distilling the resulting mixture to obtain a new form of crystalline cortisone acetate, 98 percent of the crystals thus obtained having a particle size between about forty and about sixty microns in length and furthercharacterize'd by an ultraviolet extinction E -15,800, optical rotation [u] 178 degrees (acetone), an optic axial angle of 76 degrees and the following X-ray diffraction data:

References Cited in the file of this patent 7 UNITED STATES PATENTS Macek Mar. 9, 1954 J ob n J n- 2 7 

